Many of the investigations in this genetic epidemiology project arise from observations in families at high risk of cancer or in other etiologic studies. Further analyses of a case-control study of 718 non-Hispanic white patients with cutaneous melanoma from melanoma clinics in Philadelphia and San Francisco showed modest, non-significant decreased risk of melanoma among susceptible individuals who used sunscreens most of the time. Young women were the individuals most likely to use tanning beds, and use was related to melanoma risk. Those who used tanning beds were more likely to have melanomas in sites not usually exposed to sun. These observations may help explain the increasing rates and changing distribution of melanoma among young women in the general population. Questionnaire data, tumor, and DNA from a case-control study of 183 incident melanoma cases and 179 controls conducted in North-Eastern Italy, showed a strong association between germline variants in the melanocortin-1 receptor (MC1R) gene and melanoma with somatic mutations in the BRAF oncogene, in subjects with melanoma arising on sun exposed areas of the body and with limited chronic solar damage. We confirmed this association in an independent population. Data from other Mediterranean populations have been collected and harmonized to extend the analyses of association between melanoma risk and several risk factors, also including immune-related genes. In this combined sample, we identified suggestive evidence for a role of telomere-related genes in the etiology of melanoma. Melanoma tissue specimens have been collected and analyses of melanoma lesions in relation to sun exposure, body site, nevi count, susceptibility genes and other factors is planned. One of the potential pathways that leads to the development of melanoma includes the loss of regulation of common melanocytic nevi, which acquire atypic or dysplastic characteristics that can further evolve in neoplasia. To study this pathway, we are currently collecting multiple tissue samples of normal skin, common melanocytic nevi, dysplastic nevi, melanoma and metastasis from melanoma from the same subjects from Italy and Spain. We are planning to study the expression and presence of mutations in multiple genes of the cell cycle, and transduction pathways in the serial tissue samples and germline DNA to explore the mechanisms involved in melanoma development through nevi. In addition, we are developing a new melanoma tissue-based study to identify clinically and etiologically relevant subtypes of melanoma. We plan to prospectively identify and enroll 1,500 primary melanoma patients diagnosed at University Hospitals Case Medical Center (UHCMC)/Case Comprehensive Cancer Center (Case CCC). We will classify melanomas into molecular subtypes using an integrated tumor profiling approach and will associate each molecular subtype with known melanoma risk factors (including both genetic and environmental), host pigmentation characteristics, and clinical characteristics and outcomes. Currently, we are conducting a pilot study to test the technical feasibility of this study. Relatives of 365 of the glioma cases from a DCEG comprehensive case-control study of adults with brain tumors were interviewed about personal/family medical history and other risk factors. Chordoma is a rare primary malignant bone tumor that arises mainly in the axial skeleton from rests of embryonic notochordal stem cells that failed to undergo normal regression. An expanded project has been developed to collect personal and family medical history, buccal cells and slides of tumor tissue from sporadic chordoma patients from throughout the United States and Canada. The project will collect up to 400 patients diagnosed with chordoma at any age and anatomic site. We collaborated with Yale University Tissue Microarray (TMA) core facility and successfully built TMAs of invasive tumors collected from the Polish Breast Cancer Study. Analysesof immunohistochemically (IHC) stained tumors (N=842) for 18 molecular markers involved in hormone biosynthesis, metabolism, and receptor mediated pathways suggested that risk factors for breast cancer may vary by molecular subtypes and by hormone pathways characterized by co-expression of the hormonal markers. We also stained all TMAs for six markers (ER-alpha, ER-beta, PR, HER2, EGFR, and CK5) using Automated Quantitative Analysis (AQUA) and showed that AQUA analyses of tumors represented in TMAs provide reliable, quantitative measures of marker expression. We have also compared some commercially available imaging analysis software to pathologists measurements and our data suggested that automated analysis of IHC markers represents a promising approach for analyzing large numbers of breast cancer tissues in epidemiologic investigations. We have expanded our analyses of risk factor heterogeneity by tumor subtypes to a pooled analysis of 35,568 breast cancer cases from 34 studies participating in the Breast Cancer Association Consortium (BCAC) and we found that reproductive factors and BMI are most clearly related to hormone receptor positive tumors. In addition to the analysis of invasive tumors, we are also evaluating the morphology and molecular characteristics of terminal duct lobular units (TDLUs), the structures from which breast cancers arise, in breast cancer cases. We found that TDLU involution was significantly less pronounced in breasts containing core basal phenotype (CBP) tumors as compared to luminal tumors. We are developing collaborations to confirm and extend these findings using materials from other studies. We are also measuring and analyzing marker expression in normal TDLUs in 150 Polish breast cancer cases and correlating marker data with risk factors and clinical characteristics. In addition to TMA analyses of candidate markers in fixed tissues, we have conducted tumor profiling for gene expression, CpG methylation, and copy number changes in frozen tumors from a subset of Polish breast cancer cases to better define molecular subtypes that are associated with distinct etiologic pathways. We are continuing to conduct studies using the Swedish linked registry data to define hematologic malignancies that co-aggregate in families, to detect immune-related and inflammatory conditions (based on hospitalization records) that pre-dispose to these malignancies and to define characteristics that affect progression of these conditions. We previously described increased risk of lymphoid malignancies among first-degree relatives of patients with Waldenstrom macroglobulinemia (WM) or Lymphoplasmacytic lymphoma. We recently demonstrated that relatives were not at increased risk for myeloid malignancies or for solid tumors. We found that patients with MGUS are at increased risk (2-fold, p 0.05) for subsequent infections (at 5 and 10 year follow-up). Both bacterial and viral infections were involved. Those with higher M-protein concentrations were at greatest risk. However, development of infections did not predict subsequent risk of and MGUS patient developing myeloma, WM, or related malignancy. In another study, prior infections, inflammatory diseases, and autoimmune diseases were associated with an increased risk of MGUS. A family history of autoimmune disease was also associated with subsequent MGUS suggesting some shared susceptibility. We are currently analyzing biological markers that affect progression of MGUS to myeloma and other lymphoid malignancies.